Resveratrol Protects Against Pulmonary Arterial Hypertension in Rats via Activation of Silent Information Regulator 1
Resveratrol Protects Against Pulmonary Arterial Hypertension in Rats via Activation of Silent Information Regulator 1
复制标题
白藜芦醇通过激活沉默信息调节器 1 预防大鼠肺动脉高压
DOI：
10.1159/000477115
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发表时间：
2017-01-01
影响因子：
--
通讯作者：
Fan, Yuhua
中科院分区：
文献类型：
--
作者：
Yu, Lei;Tu, Yingfeng;Fan, Yuhua
背景/目的：多酚白藜芦醇（Rev）已被发现表现出各种有益的效果，包括预防肺动脉高压（PAH）。本研究旨在探讨Rev对肺动脉高压（PAH）的作用及其可能机制，重点探讨SIRT 1（Silent Information Regulator 1）在肺动脉平滑肌细胞（PASMCs）凋亡中的作用。方法：采用低氧21天建立肺动脉高压大鼠模型。Rev和SRT 1720（一种选择性SIRT 1激活剂）通过灌胃大鼠来逆转PAH。将PASMCs缺氧24 h或48 h后分别用Rev或SRT 1720处理。Western blot检测SIRT 1蛋白的表达。进行CCK-8和划痕实验以验证细胞增殖。采用TUNEL法和流式细胞术检测PASMC凋亡。共聚焦显微镜观察线粒体通透性转换（mPT）。用Gould压力传感器测定右心室收缩压（RVSP），通过称重心肌测定右心室肥大（RVH）。结果：我们证明了Rev可以逆转肺血管重建，从而有助于减轻PAH的严重程度。SIRT 1在PAH中表达下调，而Rev对SIRT 1蛋白表达无明显影响。此外，Rev可以诱导线粒体肿胀和核固缩，导致小，致密，畸形的线粒体在大鼠暴露于缺氧单独。Rev处理在体外以剂量依赖性方式抑制PASMC增殖。SIRT 1的特异性激活剂SRT 1720可显著抑制PASMC的增殖，促进PASMC的凋亡。其机制可能与诱导PASMCs mPT损伤有关。Rev和SRT 1720治疗缓解了RVSP并降低了RVH。结论：Rev可能通过增强SIRT 1的活化，从而改善RVSP，降低RVH，从而发挥其有益作用。SIRT 1激活通过诱导mPT功能障碍增加PASMC凋亡，这可能是未来治疗PAH的新策略。
Background/Objectives: The polyphenol resveratrol (Rev) has been found to exhibit various beneficial effects including prevention of pulmonary arterial hypertension (PAH). The present study was designed to investigate the action and potential mechanism of Rev on PAH, focusing on the role of SIRT1 (Silent Information Regulator 1) in apoptosis of pulmonary artery smooth muscle cells (PASMCs). Methods: PAH rats were established by exposure to hypoxia for 21 days. Rev and SRT1720 (a selective SIRT1 activator) were used to reverse PAH by gavaging rats. PASMCs were confronted with hypoxia for 24 h or 48 h and were then treated with Rev or SRT1720 in vitro. Western blot was performed to detect the protein expression of SIRT1. CCK-8 and scratch wound experiments were carried out to verify cell proliferation. In addition, the TUNEL positive assay and flow cytometry assay were used to measure PASMC apoptosis. Mitochondrial permeability transition (mPT) was identified by confocal microscopy. Right ventricular systolic pressure (RVSP) was determined with a Gould pressure transducer, and right ventricular hypertrophy (RVH) was determined by weighing the cardiac muscle. Results: We demonstrated that Rev could reverse the remodelling of the pulmonary vasculature, thus contributing to alleviating the severity of PAH. Down-regulation of SIRT1 was observed in PAH, but administration of Rev had no obvious effect on the protein expression of SIRT1. In addition, Rev could induce mitochondrial swelling and nuclear pyknosis, leading to small, dense, and dysmorphic mitochondria in rats exposed to hypoxia alone. Rev treatment inhibited PASMC proliferation in a dose-dependent manner in vitro. Incubation with SRT1720, a specific activator of SIRT1, significantly retarded PASMC proliferation and promoted PASMC apoptosis in vitro. The mechanism could be associated with inducing mPT damage in PASMCs. Rev and SRT1720 treatment mitigated RVSP and reduced RVH. Conclusion: Rev produced a beneficial effect partially by enhancing the activation of SIRT1, thus improving RVSP and reducing RVH. SIRT1 activation increased PASMC apoptosis by inducing mPT dysfunction, which might be a novel future strategy for the treatment of PAH.